Diabetes has significant adverse serious effects on human health and accompanies various complications. There are two major types of diabetes: type I diabetes mellitus characterized by little or no insulin secretory capacity due to the destruction of pancreatic cells, and type II diabetes mellitus characterized by insulin deficiency and insulin resistance due to other causes. The incidence of type II diabetes mellitus accounts for 90% or more of total diabetic patients. Representative examples of diabetic complications include hyperlipidemia, hypertension, retinopathy and renal insufficiency (Paul Zimmer, et al., Nature, 2001, 414, 782). Sulfonylureas (stimulation of pancreatic insulin secretion), biguanides (inhibition of hepatic glucose production), α-glucosidase inhibitors (suppression of intestinal glucose absorption), etc. have been used as antidiabetic agents. Recently, peroxisome proliferator-activated receptor gamma (PPARγ) agonists (thiazolidinediones, promotion of insulin sensitivity) are drawing a great deal of attention as promising antidiabetic therapeutics. However, these antidiabetic drugs have adverse side effects such as hypoglycemia, weight gain and the like (David E. Moller, Nature, 2001, 414, 821). To this end, there is an urgent need for development of diabetes therapeutics with decreased side effects, in particular without causing hypoglycemia and weight gain.
Meanwhile, it has recently been found that dipeptidyl peptidase-IV (DPP-IV) knockout mice maintains glucagon-like protein 1 (GLP-1) activity and high insulin levels, resulting in decreased blood glucose levels, suggesting the therapeutic feasibility of DPP-IV as an antidiabetic agent (Marguet D. et al, Natl. Acad. Sci. USA, (2000) 97, 6874-6879). GLP-1 is involved in the differentiation and growth of pancreatic β-cells in vivo and plays an important role in the production and secretion of insulin. GLP-1 is inactivated by DPP-IV, and DPP-IV inhibitors have been reported to increase insulin secretion via the inhibition of GLP-1 inactivation. DPP-IV inhibitors are also being developed as anti-obesity drugs because GLP-1 contributes to satiety and fullness in rats and slows down intestinal digestion of food, resulting in weight loss. Further, many researchers and institutions have also demonstrated that DPP-IV inhibitors control blood glucose and lipid levels in animal model experiments (Pospislik J. A., et al, Diabetes, (2002) 51, 943-950). In this regard, DPP-IV inhibitors can be considered as potentially useful agents for the treatment of diabetic diseases.
To date, much research for finding and developing beneficial DPP-IV inhibitors has focused on materials in which a cyano group is introduced to a pyrrolidine ring. For example, WO 00/34241 discloses DPP-IV inhibitors represented by the following formula.

wherein R is substituted adamantyl, and n is in a range of 0 to 3.
Other inhibitors can be found in WO 04/064778, WO 03/004498, WO 03/082817, and the like. Disclosed in WO 04/064778 DPP-IV are DPP-IV inhibitors represented by the following formula.

wherein Ar is unsubstituted or substituted phenyl; R15, R16 and R17 are each independently hydrogen or alkyl; and U, V and W are each independently nitrogen, oxygen, or substituted nitrogen or carbon.
In addition, WO 03/004498 suggests DPP-IV inhibitors represented by the following formula.

wherein Ar is unsubstituted or substituted phenyl; R18 is hydrogen or alkyl; and T is nitrogen or substituted carbon.
Further, WO 03/082817 discloses DPP-IV inhibitors represented by the following formula.

wherein Ar is unsubstituted or substituted phenyl; R19, R20 and R21 are each independently hydrogen or alkyl; and Q is nitrogen or substituted carbon.
In a DPP-IV inhibitor-related patent publication WO 06/104356 assigned to the present applicant and entitled “DIPEPTIDYL PEPTIDASE-IV INHIBITING COMPOUNDS”, the present inventors have demonstrated extensive and comprehensive effects of compounds represented by Formula I′ below.
The compounds of Formula I′ are cyclic compounds having rings connected via an amide bond, which are similar to those of DPP-IV inhibitor compounds set forth in the above-mentioned patent publications; however, the molecular structures substituted with a phenyl group, which is represented as Ar or Z in the above documents, are completely different from the structures substituted with a saturated or unsaturated, 5-membered or 6-membered cyclic moiety as in the present invention. Further, to the best of our knowledge, there is yet no disclosure in the art of DPP-IV inhibitors according to the present invention, having the molecular structure where a lactam ring is substituted at the phenyl position.

Further, the inventors of the present invention discovered that the compounds of Formula I′ disclosed in the prior patent of the present applicant can exhibit significantly improved inhibitory activity and selectivity for DPP-IV through the introduction of amines having high DPP-IV inhibitory effects into substituent A and the introduction of various substituents (such as hydroxy or carbonyl group) into substituent B.
In particular, taking into consideration recent reports demonstrating that low selectivity of the conventional art for other dipeptidyl peptidases may result in a variety of adverse effects (Lankas, G. R. et al., Potential Importance of Selectivity over Dipeptidyl Peptidases 8 and 9, diabetes, 2005, 548, 2988-1994), the present invention provides highly significant results in terms of excellent pharmaceutical efficacy and high DPP-IV selectivity of the inventive compounds. Moreover, DPP-IV inhibitor compounds of the present invention having the aforementioned chemical structure and preparation methods thereof have not been disclosed in the related art.